New Approaches Targeting the Renin-Angiotensin System: Inhibition of Brain Aminopeptidase A, ACE2 Ubiquitination, and Angiotensinogen

Can J Cardiol. 2023 Dec;39(12):1900-1912. doi: 10.1016/j.cjca.2023.06.013. Epub 2023 Jun 20.


Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence, there is a need for the development of antihypertensive drugs acting on new targets to improve control of blood pressure. This review discusses novel insights (including the data of recent clinical trials) with regard to interference with the renin-angiotensin system, focusing on the enzymes aminopeptidase A and angiotensin-converting enzyme 2 (ACE2) in the brain, as well as the substrate of renin- angiotensinogen-in the liver. It raises the possibility that centrally acting amino peptidase A inhibitors (eg, firibastat), preventing the conversion of angiotensin II to angiotensin III in the brain, might be particularly useful in African Americans and patients with obesity. Firibastat additionally upregulates brain ACE2, allowing the conversion of angiotensin II to its protective metabolite angiotensin-(1-7). Furthermore, antisense oligonucleotides or small interfering ribonucleic acids suppress hepatic angiotensinogen for weeks to months after 1 injection and thus could potentially overcome adherence issues. Finally, interference with ACE2 ubiquitination is emerging as a future option for the treatment of neurogenic hypertension, given that ubiquitination resistance might upregulate ACE2 activity.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / metabolism
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Angiotensin-Converting Enzyme 2 / pharmacology
  • Angiotensin-Converting Enzyme 2 / therapeutic use
  • Angiotensinogen / metabolism
  • Angiotensinogen / pharmacology
  • Angiotensinogen / therapeutic use
  • Antihypertensive Agents / therapeutic use
  • Brain / metabolism
  • Glutamyl Aminopeptidase
  • Humans
  • Hypertension*
  • Renin-Angiotensin System* / physiology


  • firibastat
  • Antihypertensive Agents
  • Glutamyl Aminopeptidase
  • Angiotensin-Converting Enzyme 2
  • Angiotensinogen
  • Angiotensin II